Purpose

Resistance to androgen-deprivation therapies and progression to so-called castrate-resistant prostate cancer (CRPC) remain challenges in prostate cancer (PCa) management and treatment. Among other alterations, CRPC has been associated with metabolic reprogramming driven by androgens. Here, we investigated the role of androgens in regulating glutaminolysis in PCa cells and determined the relevance of this metabolic route in controlling the survival and growth of androgen-sensitive (LNCaP) and CRPC (DU145 and PC3) cells.

Methods

PCa cells (LNCaP, DU145 and PC3) and 3-month old rats were treated with 5α-dihydrotestosterone (DHT). Alternatively, LNCaP cells were exposed to the glutaminase inhibitor BPTES, alone or in combination with the anti-androgen bicalutamide. Biochemical, Western blot and extracellular flux assays were used to evaluate the viability, proliferation, migration and metabolism of PCa cells in response to DHT treatment or glutaminase inhibition.

Results

We found that DHT up-regulated the expression of the glutamine transporter ASCT2 and glutaminase, both in vitro in LNCaP cells and in vivo in rat prostate cells. BPTES diminished the viability and migration of PCa cells, while increasing caspase-3 activity. CRPC cells were found to be more dependent on glutamine and more sensitive to glutaminase inhibition. BPTES and bicalutamide co-treatment had an additive effect on suppressing LNCaP cell viability. Finally, we found that inhibition of glutaminolysis differentially affected glycolysis and lipid metabolism in both androgen-sensitive and CRPC cells.

Conclusion

Our data reveal glutaminolysis as a central metabolic route controlling PCa cell fate and highlight the relevance of targeting glutaminase for CRPC treatment.

中文翻译：

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谷氨酰胺分解是前列腺癌细胞存活和生长必不可少的代谢途径，也是 5α-二氢睾酮调节的目标

目的

对雄激素剥夺疗法的抵抗和进展为所谓的去势抵抗性前列腺癌 (CRPC) 仍然是前列腺癌 (PCa) 管理和治疗的挑战。在其他改变中，CRPC 与雄激素驱动的代谢重编程有关。在这里，我们研究了雄激素在调节 PCa 细胞中谷氨酰胺分解中的作用，并确定了这种代谢途径在控制雄激素敏感 (LNCaP) 和 CRPC（DU145 和 PC3）细胞的存活和生长方面的相关性。

方法

用 5α-二氢睾酮 (DHT) 处理 PCa 细胞（LNCaP、DU145 和 PC3）和 3 个月大的大鼠。或者，将 LNCaP 细胞暴露于谷氨酰胺酶抑制剂 BPTES，单独或与抗雄激素比卡鲁胺组合。生化、蛋白质印迹和细胞外通量测定用于评估 PCa 细胞响应 DHT 处理或谷氨酰胺酶抑制的活力、增殖、迁移和代谢。

结果

我们发现 DHT 上调了谷氨酰胺转运蛋白 ASCT2 和谷氨酰胺酶的表达，无论是在 LNCaP 细胞中的体外还是在大鼠前列腺细胞中的体内。BPTES 降低了 PCa 细胞的活力和迁移，同时增加了 caspase-3 的活性。发现 CRPC 细胞更依赖谷氨酰胺，对谷氨酰胺酶抑制更敏感。BPTES 和比卡鲁胺联合处理对抑制 LNCaP 细胞活力具有累加作用。最后，我们发现抑制谷氨酰胺分解对雄激素敏感细胞和 CRPC 细胞的糖酵解和脂质代谢有不同的影响。

结论

我们的数据显示谷氨酰胺分解是控制 PCa 细胞命运的中心代谢途径，并强调了靶向谷氨酰胺酶与 CRPC 治疗的相关性。